In 2008, three different studies found that certain genetic variants associated with nicotine dependence and smoking were also associated with lung cancer. The findings raised a question: Were the variants linked with lung cancer only through their association with smoking, a known cause of lung cancer? Or were the variants associated with lung cancer through some other pathway, independent of smoking behavior?

Now, HSPH researchers have found strong evidence suggesting that the variants are directly associated with lung cancer, independent of their effects on increasing smoking.

Even so, for people who have the variants, smoking could potentially be more lethal than for those who don’t have them.

“These genetic variants on their own can lead to increased risk of lung cancer,” said Tyler VanderWeele, associate professor of epidemiology. “What we think is going on is that if you have the variants, you smoke just a little bit more—about one cigarette more per day—but for each cigarette you smoke, you extract more nicotine and tobacco-related carcinogens. Another way of saying this is that carriers of the higher risk variant smoke more intensely and are exposed to more nicotine and toxins than those who don’t carry the variant.”

The researchers, including colleagues from HSPH and elsewhere, used new methodology and data from four case-control studies to conduct their meta-analysis, which was published May 15, 2012 in the American Journal of Epidemiology.

In smokers, about one more cigarette smoked per day is not enough to have a substantial effect on lung cancer risk, VanderWeele said. But the increased levels of nicotine and toxin extraction associated with the variants are indeed significant. “If you have the variants, smoking is even worse for you,” he said. “For the same number of cigarettes smoked, these high-risk individuals are at even higher risk.”

Roughly 56% of people have one or two copies of the smoking- and lung cancer-associated variants, VanderWeele said. Thirteen percent of people have two of them, 43% have one, and the rest don’t have any. The risk of lung cancer is about 30% higher with one copy of the variant and about 70% higher with two copies, VanderWeele said.

Interestingly, geneticist and statistician Ronald Fisher had speculated in the late 1950s that there may be a common genetic cause of both smoking and lung cancer. VanderWeele noted that the new study shows that Fisher was partially correct. While there indeed appears to be a common genetic cause of both smoking and lung cancer—independent of each other—the sizes of the effects on both “are much too small to try to explain away the causal effect of smoking itself on lung cancer,” the authors write.

The new information about the genetic variants could prove useful in the future, said VanderWeele. As genetic testing becomes more prevalent, people who have the variants could be warned that it’s even more important for them to avoid smoking than for others.